SIRT1 and Autophagy: Implications in Endocrine Disorders

Abstract

Autophagy is a cellular process involved in the selective degradation and recycling of dysfunctional intracellular components. It plays a crucial role in maintaining cellular homeostasis and survival by removing damaged and harmful proteins, lipids, and organelles. SIRT1, an NAD⁺-dependent multifunctional enzyme, is a key regulator of the autophagy process. Through its deacetylase activity, SIRT1 participates in the regulation of different steps of autophagy, from initiation to degradation. The levels and function of SIRT1 are also regulated by the autophagy process. Dysregulation in SIRT1-mediated autophagy hinders the proper functioning of the endocrine system, contributing to the onset and progression of endocrine disorders. This review provides an overview of the crosstalk between SIRT1 and autophagy and their implications in obesity, type-2 diabetes mellitus, diabetic cardiomyopathy, and hepatic steatosis.

Keywords: SIRT1; autophagy; cardiovascular disease; diabetes; diabetic cardiomyopathy; obesity.

Figure 1

Autophagy Mechanism. The autophagy process involves multi-steps which are initiation, elongation, maturation, fusion and degradation. The initiation step of mammalian autophagy involves the ULK complex (consisting of ULK1/2, ATG13, FIP200, and ATG101). The ULK complex phosphorylates Beclin1 to activate PI3K complex (composed of Beclin1-VPS34-VPS15-ATG14L). The PI3K complex then induces P3P formation, which recruits DCFP1 and WIPI for autophagosome formation. During the elongation and maturation stage, ATG7 and ATG10 help to conjugate the ATG12 to ATG5, forming an ATG5-ATG12 complex. This complex then interacts with the ATG16 to form an ATG16-ATG5-ATG12 complex that is involved in elongation and maturation of the autophagosome. LC3-I is formed by the proteolysis of pro-LC3 by ATG4. The ATG3 and ATG7 conjugate LC3-I to PE to form LC3-II that inserts into the autophagosome membrane. After the elongation and maturation, autophagosome with target cargo is trafficked to the lysosome to fuse and form an autolysosome. This process is regulated by RAB protein family, SNARE protein family, and MBP. The autolysosome then releases acidic hydrolase to degrade the inner content and the degraded cargo is released back to the cytoplasm to be reused for cellular processes.

Figure 2

Autophagy Regulation. (A) The nutritional cue leads to the mTORC1 and cAMP-dependent-PKA-dependent pathways. In a nutrient rich condition (presence of amino acids), mTORC1 inhibits the interaction between ULK complex and AMPK by phosphorylating ULK1. Under nutrient depleted condition, mTORC1 is inactivated to allow the AMPK to interact with ULK1 for autophagy initiation. Under nutrition rich condition (presence of glucose), PKA inhibits autophagy process by phosphorylating LC3, activating mTORC1, and inactivating AMPK. (B) Under ATP depleted condition, LKB1 senses the decreased ATP/AMP ratio and activates AMPK, which inactivates mTORC1 by activating TSC2 and phosphorylating Raptor of mTORC1. This eventually leads to the upregulation of autophagy. (C) Under ER stress condition, the cytosolic Ca⁺² level increases to activate CAMKK2/CaMKKβ that activates AMPK. AMPK helps to inhibit mTORC1 activity to induce autophagy by activating TSC2 and phosphorylating Raptor. The ER stress condition also triggers an UPR process that responds to an accumulation of unfolded proteins. UPR activates PERK-eIF2a-ATF4 pathway, which upregulates the production of ATGs necessary for autophagy process. (D) Under hypoxia condition, there is an increased expression of HIF1 that upregulates the expression of BNIP-3. BNIP3 promoter contains HRE that is activated by the HIF1. The BH3 functional domain of BNIP3 competitively interferes with the interaction between the Beclin1 and Bcl-2. This disruption liberates Beclin1 to be used for the autophagy initiation process.

Figure 3

SIRT1-mediated autophagy initiation regulation. (A) Under starved condition, Deacetylase activity of SIRT1 also increases the stability of TSC2 to promote GTP hydrolysis of Rheb. Rheb suppression downregulates the mTOR signaling process. (B) Under hypoxia condition, SIRT1 deacetylases FOXO3 to bind to BNIP-3 promotor and promote BNIP-3 expression.

Figure 4

SIRT1-mediated autophagy elongation and maturation regulation. The BNIP-3 expression then induces autophagy by using its functional BH3 domain to dissociate Beclin1 from the Bcl-2-Beclin1 complex. (A) Under nutrient rich condition, EP300 acetyltransferase inhibits the elongation of the autophagosome by acetylating the ATG5, 7, and 12. (B) Under nutrient deprived state, SIRT1 directly deacetylates these ATGs to form ATG 16-5-12 complex that aids in the elongation of the autophagic vesicle. (C) Under starved condition, SIRT1 directly deacetylates the nuclear LC3-I. The deacetylated LC3-I then interacts with DOR protein and this interaction between the deacetylated LC3-I and DOR protein allows the nuclear export of LC3-I. The deacetylation of LC3-I also helps LC3-I to interact with ATG7. Through this interaction, the translocated LC3-I conjugates to PE, forming LC3-II which is inserted to the autophagosome membrane to help selective targeting of the cargo.

Figure 5

SIRT1-mediated autophagy fusion regulation. Under nutrient-starved condition, SIRT1 mediates the autophagy and lysosome fusion by deacetylating FOXO1. The deacetylation of FOXO1 is necessary for the expression of Rab7 that helps to regulate this microtubule-dependent bidirectional transport of the autophagosome to the lysosome.